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Radiotherapy-induced brain injury (RIBI) is a chronic side effect that affects brain tumor survivors treated with radiotherapy. Neuroinflammation is a key contributor to RIBI. Thus, imaging methods capable of noninvasively monitoring neuroinflammation are needed. Although positron emission tomography (PET)-based radiotracers exist for imaging neuroinflammation, PET involves ionizing radiation which could be detrimental to pediatric patients already facing the risk of RIBI. Here, we evaluated the feasibility of developing contrast-enhanced T 1 W MRI as a predictive biomarker of neuroinflammation in RIBI. Four groups of eight-week-old female BALB/c mice were stereotactically irradiated at 80 Gy and monitored longitudinally for neuroinflammation using 11 C-DPA-713 PET; 11 C-CPPC PET; gadoteridol-based contrast-enhanced T 1 -weighted MRI; and TSPO, CD68, IBA1 immunohistochemistry. Our results showed that contrast-enhanced T 1 W MRI was as effective as 11 C-DPA-713 PET; 11 C-CPPC PET and immunohistochemistry ( P  < 0.05, n  = 3) in predicting neuroinflammation, by detecting subtle changes in the blood-brain barrier permeability that affected neuroinflammation changes.

Background The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve. Main messages The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer’s disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction. Conclusions There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer’s disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer’s disease but still require further investigation.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke.

In response to physiological and psychogenic stressors, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates the systemic release of glucocorticoids (GCs). By virtue of nearly ubiquitous expression of the GC receptor and the multifaceted metabolic, cardiovascular, cognitive, and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory, and hematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.

Ferroptosis is a form of cellular death involved in the origin, progression, but also regulation of several human diseases. Its regulatory role in the gut-liver-brain axis (GLBA) has not been clarified. Therefore, we sought to summarize the possible correlations between ferroptosis and the GLBA. In this review, we first introduce the phenotype and the main mechanisms of this relatively newly described form of regulated cell death. Then, we analyse the anatomy of the GLBA, describing the connections between the gut and the liver, followed by the anatomical pathways from the gut to the brain and from the liver to the brain. After the morphological aspects, we summarize the main biological modulators of the GLBA, highlighting their physiological and pathological roles. In the end, we discuss in detail the regulatory role of ferroptosis on neuroinflammation and oxidative stress along GLBA, highlighting the key aspects that could be of significant clinical importance as future diagnostic and therapeutic targets.

The discovery of novel biomarkers and therapeutic targets is essential for advancing multiple sclerosis (MS) treatment strategies. Lipocalin-2 (LCN2), a 25-kDa glycoprotein, has gained considerable attention for its diverse roles in immune regulation and neuroinflammation. Its expression varies across MS subtypes and disease stages, influencing both peripheral immune responses and central nervous system pathology. Growing evidence has demonstrated the involvement of LCN2 in modulating immune cell function, glial reactivity, and blood-brain barrier integrity. Clinical studies have consistently correlated LCN2 levels in patient biofluids with disease parameters, supporting its potential as a biomarker. Moreover, experimental studies targeting LCN2 have shown promising therapeutic potential. This review examines the role of LCN2 in MS, focusing on its impact on peripheral immune cells, neuroinflammation, and its viability as a biomarker and therapeutic target. We also discuss the relevance of LCN2-targeting therapies within the evolving MS treatment landscape, underscoring the need for further research in this area.

BackgroundMénière’s disease (MD) is a complex disorder whose pathogenesis extends beyond endolymphatic hydrops to involve dysregulated immune responses. While a subset of patients exhibits a “low-cytokine phenotype” during remission, the mechanisms underlying the transition to acute inflammatory attacks triggered by environmental factors remain poorly understood.MethodsWe employed an integrative multi-omics approach to explore the immune microenvironment of MD. This included bioinformatic analysis of differentially expressed genes (DEGs) from GSE109558, featuring PBMCs from MD patients and healthy controls stimulated with Aspergillus or Penicillium. Protein-protein interaction (PPI) networks, immune infiltration analysis, and single-cell RNA sequencing (GSE269117) were utilized to identify hub genes and cellular interactions. Key findings were validated in an independent cohort through measurement of serum cytokines, in vitro macrophage stimulation assays, and immunofluorescence staining.ResultsBioinformatic analysis revealed a latent hyperinflammatory potential in MD PBMCs, which was unmasked upon fungal challenge, showing significant enrichment in neutrophil chemotaxis and NF-κB pathways. We identified 20 hub genes, with CXCL8 emerging as a top candidate. Single-cell sequencing and CellChat analysis pinpointed macrophages as the dominant source of CXCL8 and key orchestrators of intercellular communication, notably via the ALCAM-CD6 pathway with T cells. In vitro verification confirmed this macrophage-driven inflammatory cascade response. Under the stimulation of LPS/β -glucan, the level of CXCL8 secreted by macrophages in MD patients increased (p < 0.01), while there was no difference before and after stimulation in the healthy control group. Serum levels of CXCL8, IL-6, and IL-17A were also significantly elevated in MD patients during attacks.ConclusionOur findings support a novel “hypoimmune-hyperinflammatory switch” model in MD, wherein macrophages play an important role in initiating and amplifying inflammatory responses to environmental triggers via CXCL8 production and cellular crosstalk. This refined understanding of the immune axis in MD provides a foundational basis for developing targeted immunomodulatory therapies.

BackgroundA number of microRNAs are implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. Particularly, miR-34a levels in the brain are increased in Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis is unknown.MethodsIn order to investigate the role of miR-34a in AD, we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). Their cognitive function was evaluated by Morris water maze. Immunohistochemistry and immunofluorescence were used for neuropathological evaluation. Bulk RNA-seq followed by bioinformatics was used for hippocampal transcriptomics. The effect of miR-34a knockdown on expression of interferon-stimulated genes (ISG) was determined using cultured microglial cells and quantitative PCR.ResultsMiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified “cellular response to type I interferon” and “type I interferon signaling pathway” as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 and primary microglia.ConclusionOur results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.

Occupational or environmental exposure to manganese (Mn) can lead to the development of \"Manganism,\" a neurological condition showing certain motor symptoms similar to Parkinson's disease (PD). Like PD, Mn toxicity is seen in the central nervous system mainly affecting nigrostriatal neuronal circuitry and subsequent behavioral and motor impairments. Since the first report of Mn-induced toxicity in 1837, various experimental and epidemiological studies have been conducted to understand this disorder. While early investigations focused on the impact of high concentrations of Mn on the mitochondria and subsequent oxidative stress, current studies have attempted to elucidate the cellular and molecular pathways involved in Mn toxicity. In fact, recent reports suggest the involvement of Mn in the misfolding of proteins such as α-synuclein and amyloid, thus providing credence to the theory that environmental exposure to toxicants can either initiate or propagate neurodegenerative processes by interfering with disease-specific proteins. Besides manganism and PD, Mn has also been implicated in other neurological diseases such as Huntington's and prion diseases. While many reviews have focused on Mn homeostasis, the aim of this review is to concisely synthesize what we know about its effect primarily on the nervous system with respect to its role in protein misfolding, mitochondrial dysfunction, and consequently, neuroinflammation and neurodegeneration. Based on the current evidence, we propose a 'Mn Mechanistic Neurotoxic Triad' comprising (1) mitochondrial dysfunction and oxidative stress, (2) protein trafficking and misfolding, and (3) neuroinflammation.